[9] After the complete assemblage, the conformational changes in IL-4RI or IL-4RII tails leads to the intracellular signaling, starting with the auto and cross-phosphorylation of associated Jak kinases (Jak3 for IL-2Rγc, Jak1 for IL-4Rα, Jak2 and Tyk2 for IL-13Rα1),[10] and followed by phosphorylation of intracellular domains of IL-4Rα in critical Y residues which are therefore activated to form the docking sites for downstream signalling molecules endowed with SH domains.
[11] Activated STAT6 molecules form dimers which translocate to the nucleus to bind responsive elements (e.g. CD23 promoter in B cells,[12] arginase1 enhancer in macrophages[13] ) The binding affinity of IL-4 for IL-4Rα is much higher than IL-13 for the IL-13Rα1, hence IL-4 would out-compete IL-13 for receptor availability within IL4R2 at parity of concentration.
IL-13Rα2 presents 35% homology with IL-13Rα1 and it is expressed mostly in structural cell (but also has been identified in fibroblasts and, only in mice, in soluble form).
IL-13 signalling through IL-13Rα2 and AP1-driven TGF-β production has been initially reported in monocytes and then confirmed in mouse models.
[17][18] According these studies, IL-13, through the over-expression (TNF-α induced) of IL-13Rα2 would be able to activate AP-1 signalling and production of TGF-β, driving pro-fibrotic effects.
Some recent works is evidencing how a wide range of signals can be actually activated by this receptor (e.g. WNT/β-Catenin, MAPK/ERK, AKT/PKB, Src/FAK, PIP3K ) in normal or pathologic environments.